Publications by authors named "Thomas Krausz"

113 Publications

Comparison of Nuclear Grade, Necrosis, and Histologic Subtype Between Biopsy and Resection in Pleural Malignant Mesothelioma.

Am J Clin Pathol 2021 May 12. Epub 2021 May 12.

Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Objectives: Numerous studies on malignant mesothelioma (MM) highlight the prognostic importance of histologic subtype, nuclear grade, and necrosis. This study compares these parameters in paired biopsy and resection specimens of pleural MM.

Methods: Histologic subtype, percentage of epithelioid morphology, nuclear grade, and the presence or absence of necrosis were compared in 429 paired biopsies and resection specimens of pleural MM from 19 institutions.

Results: Histologic subtype was concordant in 81% of cases (κ = 0.58). When compared with resection specimens, epithelioid morphology at biopsy had a positive predictive value (PPV) of 78.9% and a negative predictive value (NPV) of 93.5%; sarcomatoid morphology showed high PPV (92.9%) and NPV (99.3%), and biphasic morphology PPV was 89.7% and NPV was 79.7%. Agreement of the percentage of epithelioid morphology was fair (κ = 0.27). Nuclear grade and necrosis were concordant in 75% (κ = 0.59) and 81% (κ = 0.53) of cases, respectively. Nuclear grade showed moderate (κ = 0.53) and substantial (κ = 0.67) agreement from patients with and without neoadjuvant therapy, respectively, and necrosis showed moderate (κ = 0.47 and κ = 0.60) agreement, respectively, in the same subsets of paired specimens.

Conclusions: Paired biopsy-resection specimens from pleural MM show overall moderate agreement in pathologic parameters. These findings may help guide postbiopsy management and triage of patients with MM.
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http://dx.doi.org/10.1093/ajcp/aqab054DOI Listing
May 2021

A series of COVID-19 autopsies with clinical and pathologic comparisons to both seasonal and pandemic influenza.

J Pathol Clin Res 2021 May 7. Epub 2021 May 7.

Department of Pathology, University of Chicago Medical Center, Chicago, IL, USA.

Autopsies of patients who have died from COVID-19 have been crucial in delineating patterns of injury associated with SARS-CoV-2 infection. Despite their utility, comprehensive autopsy studies are somewhat lacking relative to the global burden of disease, and very few comprehensive studies contextualize the findings to other fatal viral infections. We developed a novel autopsy protocol in order to perform postmortem examinations on victims of COVID-19 and herein describe detailed clinical information, gross findings, and histologic features observed in the first 16 complete COVID-19 autopsies. We also critically evaluated the role of ancillary studies used to establish a diagnosis of COVID-19 at autopsy, including immunohistochemistry (IHC), in situ hybridization (ISH), and electron microscopy (EM). IHC and ISH targeting SARS-CoV-2 were comparable in terms of the location and number of infected cells in lung tissue; however, nonspecific staining of bacteria was seen occasionally with IHC. EM was unrevealing in blindly sampled tissues. We then compared the clinical and histologic features present in this series to six archival cases of fatal seasonal influenza and six archival cases of pandemic influenza from the fourth wave of the 'Spanish Flu' in the winter of 1920. In addition to routine histology, the inflammatory infiltrates in the lungs of COVID-19 and seasonal influenza victims were compared using quantitative IHC. Our results demonstrate that the clinical and histologic features of COVID-19 are similar to those seen in fatal cases of influenza, and the two diseases tend to overlap histologically. There was no significant difference in the composition of the inflammatory infiltrate in COVID-19 and influenza at sites of acute lung injury at the time of autopsy. Our study underscores the relatively nonspecific clinical features and pathologic changes shared between severe cases of COVID-19 and influenza, while also providing important caveats to ancillary methods of viral detection.
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http://dx.doi.org/10.1002/cjp2.220DOI Listing
May 2021

Pembrolizumab Plus Ipilimumab Following Anti-PD-1/L1 Failure in Melanoma.

J Clin Oncol 2021 May 4:JCO2100079. Epub 2021 May 4.

UPMC Hillman Cancer Center, Pittsburgh, PA.

Purpose: Combination of antiprogrammed cell death protein-1 (PD-1) plus anti-cytotoxic T-cell lymphocyte-4 (anti-CTLA-4) immunotherapy shows greater response rates (RRs) than anti-PD-1 antibody alone in melanoma, but RR after initial anti-PD-1 and programmed death ligand-1 (PD-L1) antibody progression awaits robust investigation. Anti-CTLA-4 antibody alone after anti-PD-1/L1 antibody progression has a historical RR of 13%. We report the results of the first prospective clinical trial evaluating ipilimumab 1 mg/kg plus pembrolizumab following progression on anti-PD-1 immunotherapy.

Methods: Patients with advanced melanoma who had progressed on anti-PD-1/L1 antibody as immediate prior therapy (including non-anti-CTLA-4 antibody combinations) were eligible. Patients received pembrolizumab 200 mg plus ipilimumab 1 mg/kg once every 3 weeks for four doses, followed by pembrolizumab monotherapy. The primary end point was RR by irRECIST. After 35 patients, the trial met the primary end point and was expanded to enroll a total of 70 patients to better estimate the RR.

Results: Prior treatments included 60 on anti-PD-1 antibody alone and 10 on anti-PD-1/L1 antibody-based combinations. Thirteen patients had progressed in the adjuvant setting. The median length of prior treatment with anti-PD-1/L1 antibody was 4.8 months. Response assessments included five complete and 15 partial responses, making the irRECIST RR 29% among the entire trial population. The median progression-free survival was 5.0 months, and the median overall survival was 24.7 months. The median duration of response was 16.6 months. There was no difference in median time on prior anti-PD1/L1 or time to PD1 + CTLA4 initiation between responders and nonresponders. Grade 3-4 drug-related adverse events occurred in 27% of patients. Responses occurred in PD-L1-negative, non-T-cell-inflamed, and intermediate tumor phenotypes.

Conclusion: To our knowledge, this is the first prospective study in melanoma of pembrolizumab plus low-dose ipilimumab after anti-PD-1/L1 immunotherapy failure, demonstrating significant antitumor activity and tolerability.
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http://dx.doi.org/10.1200/JCO.21.00079DOI Listing
May 2021

The concept of mesothelioma in situ, with consideration of its potential impact on cytology diagnosis.

Pathology 2021 Jun 26;53(4):446-453. Epub 2021 Mar 26.

Department of Pathology, University of Chicago, Chicago, IL, USA.

Diffuse malignant mesothelioma (MM) is an incurable tumour of the serosal membranes, which is often caused by exposure to asbestos and commonly diagnosed at advanced stage. Malignant mesothelioma in situ (MMIS) is now included as diagnostic category by the World Health Organization (WHO). However, our international survey of 34 pulmonary pathologists with an interest in MM diagnosis highlights inconsistency regarding how the diagnosis is being made by experts, despite published guidelines. Whilst the WHO restricts the diagnosis to surgical samples, the very concept has implication for cytological diagnosis, which is already regarded as controversial in itself by some. MMIS is currently only applicable as precursor to MM with an epithelioid component, and raises the possibility for different molecular pathways for different histological MM subtypes. The clinical implications of MMIS at this stage are uncertain, but aggressive therapies are being initiated in some instances. Based on the results of the survey we here present a critical appraisal of the concept, its clinical and conceptual implications and provide practice suggestions for diagnosis. A low threshold for ancillary testing is suggested. The designations of 'malignant mesothelioma, cannot exclude MMIS' or 'atypical mesothelial proliferation with molecular indicators of malignancy, so-called MMIS' could be used on cytology samples, adding 'no evidence of invasion in sample provided' for surgical samples. Clinical and radiological correlation are integral to diagnosis and best done at multidisciplinary meetings. Finally, collaborative studies are required to improve our understanding of MMIS.
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http://dx.doi.org/10.1016/j.pathol.2020.12.005DOI Listing
June 2021

A Distinctive Adnexal (Usually Paratubal) Neoplasm Often Associated With Peutz-Jeghers Syndrome and Characterized by STK11 Alterations (STK11 Adnexal Tumor): A Report of 22 Cases.

Am J Surg Pathol 2021 Jan 29. Epub 2021 Jan 29.

University of Chicago Medical Center, Chicago, IL Massachusetts General Hospital, Harvard Medical School, Boston, MA Stanford University School of Medicine, Stanford, CA Institute Bergonié, Comprehensive Cancer Center, Bordeaux, France Memorial Sloan Kettering Cancer Center, New York, NY Spectrum Healthcare Partners, Portland, ME Mayo Clinic, Rochester, MN Lund University, Lund, Sweden Baylor College of Medicine, Houston, TX Maastricht University Medical Center, Maastricht, The Netherlands Imperial College London, London, UK Catholic University of Sacred Heart, Rome, Italy Belfast Health and Social Care Trust, Belfast, Northern Ireland.

We describe 22 examples of a novel, usually paratubal, adnexal tumor associated with Peutz-Jeghers syndrome in nearly 50% of cases that harbored STK11 alterations in all tested (n=21). The patients ranged from 17 to 66 years (median=39 y) and the tumors from 4.5 to 25.5 cm (median=11 cm). Most (n=18) were paratubal, with metastases noted in 11/22 (50%) and recurrences in 12/15 (80%). Morphologically, they were characterized by interanastomosing cords and trabeculae of predominantly epithelioid cells, set in a variably prominent myxoid to focally edematous stroma, that often merged to form tubular, cystic, cribriform, and microacinar formations, reminiscent of salivary gland-type tumors. The tumor cells were uniformly atypical, often with prominent nucleoli and a variable mitotic index (median=9/10 HPFs). The tumors were usually positive to a variable extent for epithelial (CAM5.2, AE1/AE3, cytokeratin 7), sex cord (calretinin, inhibin, WT1), and mesothelial (calretinin, D2-40) markers, as well as hormone receptors. PAX8, SF1, and GATA-3 were rarely positive, while claudin-4, FOXL2, and TTF-1 were consistently negative. All sequenced tumors (n=21) harbored alterations in STK11, often with a loss of heterozygosity event. There were no other recurrently mutated genes. Recurrent copy number alterations included loss of 1p and 11q, and gain of 1q, 15q, and 15p. Despite an extensive morphologic, immunohistochemical, and molecular evaluation, we are unable to determine with certainty the histogenesis of this unique tumor. Wolffian, sex cord stromal, epithelial, and mesothelial origins were considered. We propose the term STK11 adnexal tumor to describe this novel entity and emphasize the importance of genetic counseling in these patients as a significant number of neoplasms occur in association with Peutz-Jeghers syndrome.
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http://dx.doi.org/10.1097/PAS.0000000000001677DOI Listing
January 2021

A Descriptive and Quantitative Immunohistochemical Study Demonstrating a Spectrum of Platelet Recruitment Patterns Across Pulmonary Infections Including COVID-19.

Am J Clin Pathol 2021 02;155(3):354-363

Department of Pathology, University of Chicago Medical Center, Chicago, IL.

Objectives: Pulmonary platelet deposition and microangiopathy are increasingly recognized components of coronavirus disease 2019 (COVID-19) infection. Thrombosis is a known component of sepsis and disseminated intravascular coagulation. We sought to compare the level of platelet deposition in the pulmonary vasculature in cases of confirmed COVID-19 infection to other lung injuries and infections.

Methods: Immunohistochemistry was performed on 27 autopsy cases and 2 surgical pathology cases targeting CD61. Multiple cases of normal lung, diffuse alveolar damage, COVID-19, influenza, and bacterial and fungal infections, as well as one case of pulmonary emboli, were included. The levels of CD61 staining were compared quantitatively in the autopsy cases, and patterns of staining were described.

Results: Nearly all specimens exhibited an increase in CD61 staining relative to control lung tissue. The area of CD61 staining in COVID-19 infection was higher than influenza but still comparable to many other infectious diseases. Cases of aspiration pneumonia, Staphylococcus aureus infection, and blastomycosis exhibited the highest levels of CD61 staining.

Conclusions: Platelet deposition is a phenomenon common to many pulmonary insults. A spectrum of staining patterns was observed, suggestive of pathogen-specific mechanisms of platelet deposition. Further study into the mechanisms driving platelet deposition in pulmonary injuries and infections is warranted.
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http://dx.doi.org/10.1093/ajcp/aqaa230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717231PMC
February 2021

Malignant peritoneal mesothelioma: prognostic significance of clinical and pathologic parameters and validation of a nuclear-grading system in a multi-institutional series of 225 cases.

Mod Pathol 2021 02 15;34(2):380-395. Epub 2020 Oct 15.

Department of Pathology, University of Chicago, Chicago, IL, USA.

Malignant peritoneal mesothelioma historically carried a grim prognosis, but outcomes have improved substantially in recent decades. The prognostic significance of clinical, morphologic, and immunophenotypic features remains ill-defined. This multi-institutional cohort comprises 225 malignant peritoneal mesotheliomas, which were assessed for 21 clinical, morphologic, and immunohistochemical parameters. For epithelioid mesotheliomas, combining nuclear pleomorphism and mitotic index yielded a composite nuclear grade, using a previously standardized grading system. Correlation of clinical, morphologic, and immunohistochemical parameters with overall and disease-free survival was examined by univariate and multivariate analyses. On univariate analysis, longer overall survival was significantly associated with diagnosis after 2000 (P = 0.0001), age <60 years (P = 0.0001), ECOG performance status 0 or 1 (P = 0.01), absence of radiographic lymph-node metastasis (P = 0.04), cytoreduction surgery (P < 0.0001), hyperthermic intraperitoneal chemotherapy (P = 0.0001), peritoneal carcinomatosis index <27 (P = 0.01), absence of necrosis (P = 0.007), and epithelioid histotype (P < 0.0001). Among epithelioid malignant mesotheliomas only, longer overall survival was further associated with female sex (P = 0.03), tubulopapillary architecture (P = 0.005), low nuclear pleomorphism (P < 0.0001), low mitotic index (P = 0.0007), and low composite nuclear grade (P < 0.0001). On multivariate analyses, the low composite nuclear grade was independently associated with longer overall and disease-free survival (P < 0.0001). Our data further clarify the interactions of clinical and pathologic features in peritoneal mesothelioma prognosis and validate the prognostic significance of a standardized nuclear-grading system in epithelioid malignant mesothelioma of the peritoneum.
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http://dx.doi.org/10.1038/s41379-020-00688-4DOI Listing
February 2021

Improved Survival Associated with Local Tumor Response Following Multisite Radiotherapy and Pembrolizumab: Secondary Analysis of a Phase I Trial.

Clin Cancer Res 2020 12 7;26(24):6437-6444. Epub 2020 Oct 7.

University of Chicago Medicine, Chicago, Illinois.

Purpose: Multisite stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) has demonstrated safety in advanced solid tumors (ASTs). However, no studies have examined the relationships between irradiated tumor response, SBRT-induced tumor gene expression, and overall survival (OS).

Patients And Methods: Patients with AST received SBRT (30-50 Gy in 3-5 fractions) to two to four metastases followed by pembrolizumab (200 mg i.v. every 3 weeks). SBRT was prescribed to a maximum tumor volume of 65 mL. Small metastases received the complete prescribed coverage (complete-Rx), while larger metastases received partial coverage (partial-Rx). Treated metastasis control (TMC) was defined as a lack of progression for an irradiated metastasis. Landmark analysis was used to assess the relationship between TMC and OS. Thirty-five biopsies were obtained from 24 patients: 19 pre-SBRT and 16 post-SBRT (11 matched) prior to pembrolizumab and were analyzed via RNA microarray.

Results: Sixty-eight patients (139 metastases) were enrolled with a median follow-up of 10.4 months. One-year TMC was 89.5% with no difference between complete-Rx or partial-Rx. On multivariable analysis, TMC was independently associated with a reduced risk for death (HR, 0.36; 95% confidence interval, 0.17-0.75; = 0.006). SBRT increased expression of innate and adaptive immune genes and concomitantly decreased expression of cell cycle and DNA repair genes in the irradiated tumors. Elevated post-SBRT expression of correlated with increased expression of cytolytic T-cell genes and irradiated tumor response.

Conclusions: In the context of SBRT+P, TMC independently correlates with OS. SBRT impacts intratumoral immune gene expression associated with TMC. Randomized trials are needed to validate these findings.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1790DOI Listing
December 2020

Biological Mechanisms and Clinical Significance of Mutations in Human Cancer.

Cancer Discov 2020 08 20;10(8):1103-1120. Epub 2020 Jul 20.

University of Hawai'i Cancer Center, Honolulu, Hawai'i.

Among more than 200 -mutant families affected by the "BAP1 cancer syndrome," nearly all individuals inheriting a mutant allele developed one or more malignancies during their lifetime, mostly uveal and cutaneous melanoma, mesothelioma, and clear-cell renal cell carcinoma. These cancer types are also those that, when they occur sporadically, are more likely to carry somatic biallelic mutations. Mechanistic studies revealed that the tumor suppressor function of BAP1 is linked to its dual activity in the nucleus, where it is implicated in a variety of processes including DNA repair and transcription, and in the cytoplasm, where it regulates cell death and mitochondrial metabolism. BAP1 activity in tumor suppression is cell type- and context-dependent. BAP1 has emerged as a critical tumor suppressor across multiple cancer types, predisposing to tumor development when mutated in the germline as well as somatically. Moreover, has emerged as a key regulator of gene-environment interaction..
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http://dx.doi.org/10.1158/2159-8290.CD-19-1220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006752PMC
August 2020

Uterine Tumor Resembling Ovarian Sex Cord Stromal Tumor (UTROSCT): A Series of 3 Cases With Extensive Rhabdoid Differentiation, Malignant Behavior, and ESR1-NCOA2 Fusions.

Am J Surg Pathol 2020 11;44(11):1563-1572

Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

ESR1 and GREB1 fusions have recently been described in uterine tumor resembling ovarian sex cord tumor (UTROSCT). Thus far, recurrences have been documented in a subset of those harboring GREB1 fusions, but not in those with ESR1 rearrangements. Here we describe the clinicopathologic features of 3 recurrent UTROSCTs with striking rhabdoid morphology (an unusual feature of these tumors overall) and ESR1-NCOA2 fusions. The patients were 32, 37, and 54 years at initial diagnosis and first recurrence occurred at 7, 9, and 32 years. The primary tumors (available in two cases) were centered in the myometrium and showed infiltrative borders. They predominantly grew in sheets and cords, but also had a pseudopapillary appearance. Cells were uniformly epithelioid with eccentric nuclei, prominent nucleoli, abundant eosinophilic globular/glassy (rhabdoid) cytoplasm, and infrequent mitoses (≤4/10 high-power fields [HPFs]). Recurrences were morphologically identical to the primary tumors, but demonstrated brisk mitotic activity (≥16/10 HPFs). The third tumor (with only recurrences available) had multiple patterns, including diffuse, corded, trabecular, and a focal retiform growth. Rhabdoid cells were conspicuous, but only comprised ~50% of the tumor, and mitoses numbered up to 2/10 HPFs. All tumors were strongly and diffusely positive for WT1, CAM5.2, ER, and PR, but negative for inhibin. Diffuse calretinin and desmin expression, as well as focal melan-A positivity, was noted in one tumor, but was negative in the others. In all 3 tumors, INI-1 and BRG-1 were retained, and ESR1-NCOA2 fusions were detected by targeted RNA sequencing. This study is the first to highlight an association between UTROSCTs with extensive rhabdoid differentiation, ESR1-NCOA2 fusions, and aggressive behavior. UTROSCTs are considered neoplasms of uncertain malignant potential, but have a benign course in most cases. Thus, it is important to be aware of these specific features and recommend long-term follow-up due to their propensity for late recurrences.
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http://dx.doi.org/10.1097/PAS.0000000000001543DOI Listing
November 2020

Cooperation of genes in HPV16 E6/E7-dependent cervicovaginal carcinogenesis trackable by endoscopy and independent of exogenous estrogens or carcinogens.

Carcinogenesis 2020 11;41(11):1605-1615

Department of Pathology, The University of Chicago, Chicago, IL, USA.

Human papillomavirus (HPV) infection is necessary but insufficient for progression of epithelial cells from dysplasia to carcinoma-in situ (CIS) to invasive cancer. The combination of mutant cellular and viral oncogenes that regulate progression of cervical cancer (CC) remains unclear. Using combinations of HPV16 E6/E7 (E+), mutant Kras (mKras) (K+) and/or loss of Pten (P-/-), we generated autochthonous models of CC without exogenous estrogen, carcinogen or promoters. Furthermore, intravaginal instillation of adenoCre virus enabled focal activation of the oncogenes/inactivation of the tumor suppressor gene. In P+/+ mice, E6/E7 alone (P+/+E+K-) failed to cause premalignant changes, while mKras alone (P+/+E-K+) caused persistent mucosal abnormalities in about one-third of mice, but no cancers. To develop cancer, P+/+ mice needed both E6/E7 and mKras expression. Longitudinal endoscopies of P+/+E+K+ mice predicted carcinoma development by detection of mucosal lesions, found on an average of 23 weeks prior to death, unlike longitudinal quantitative PCRs of vaginal lavage samples from the same mice. Endoscopy revealed that individual mice differed widely in the time required for mucosal lesions to appear after adenoCre and in the time required for these lesions to progress to cancer. These cancers developed in the transition zone that extends, unlike in women, from the murine cervix to the distal vagina. The P-/-E+K+ genotype led to precipitous cancer development within a few weeks and E6/E7-independent cancer development occurred in the P-/-E-K+ genotype. In the P-/-E+K- genotype, mice only developed CIS. Thus, distinct combinations of viral and cellular oncogenes are involved in distinct steps in cervical carcinogenesis.
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http://dx.doi.org/10.1093/carcin/bgaa027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896110PMC
November 2020

Application of immunohistochemistry in diagnosis and management of malignant mesothelioma.

Transl Lung Cancer Res 2020 Feb;9(Suppl 1):S3-S27

Department of Pathology, University of Chicago, Chicago, IL 60637, USA.

Immunohistochemistry plays an indispensable role in accurate diagnosis of malignant mesothelioma, particularly in morphologically challenging cases and in biopsy and cytology specimens, where tumor architecture is difficult or impossible to evaluate. Application of a targeted panel of mesothelial- and epithelial-specific markers permits correct identification of tumor lineage in the vast majority of cases. An immunopanel including two mesothelial markers (calretinin, CK5/6, WT-1, or D2-40) and two epithelial markers (MOC-31 and claudin-4) offers good sensitivity and specificity, with adjustments as appropriate for the differential diagnosis. Once mesothelial lineage is established, malignancy-specific studies can help verify a diagnosis of malignant mesothelioma. BAP1 loss, homozygous deletion, and MTAP loss are highly specific markers of malignancy in a mesothelial lesion, and they attain acceptable diagnostic sensitivity when applied as a diagnostic panel. Novel markers of malignancy, such as 5-hmC loss and increased EZH2 expression, are promising, but have not yet achieved widespread clinical adoption. Some diagnostic markers also have prognostic significance, and PD-L1 immunohistochemistry may predict tumor response to immunotherapy. Application and interpretation of these immnuomarkers should always be guided by clinical history, radiographic findings, and above all histomorphology.
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http://dx.doi.org/10.21037/tlcr.2019.11.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082260PMC
February 2020

Female adnexal tumors of probable Wolffian origin: morphological, immunohistochemical, and molecular analysis of 15 cases.

Mod Pathol 2020 04 7;33(4):734-747. Epub 2019 Oct 7.

Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.

Female adnexal tumors of probable Wolffian origin are rare and present a diagnostic challenge due to their morphological and immunohistochemical overlap with more common ovarian and broad ligament entities. We evaluated the morphological, immunohistochemical, and molecular features of 15 tumors of probable Wolffian origin. Patients ranged from 32 to 69 (mean 47) years and tumors from 1.8 to 30 (mean 10) cm. All except one arose in para-adnexal soft tissues. Follow-up was available for six patients, five of whom were alive and well, while the sixth, who had extra-adnexal disease at diagnosis, died from unrelated causes. The following patterns were noted: tubular (all tumors), solid 11/15 (73%), sieve-like 7/15 (47%), and reticular 1/15 (7%). A myxoid background was present in 3/15 (20%) of tumors and eosinophilic luminal secretions in 11/15 (73%). Most tumors (12/15, 80%) had low-grade nuclear atypia, while three showed foci with scattered high-grade atypia. Mitotic index ranged from 0 to 17 (mean 4) per ten high-power fields. Tumors were positive for pankeratin and negative for TTF-1. EMA, GATA3, and PAX8 were positive in 2/10 (20%; focal), 3/15 (20%; focal), and 1/15 (7%; focal) of tumors, respectively. CD10, SF-1, calretinin, inhibin, ER, PR, cytokeratin 7, and WT1 were variably expressed. Pathogenic mutations were rare and included STK11 (n = 3), APC (n = 1), and MBD4 (n = 1). Copy number variations were detected in the three tumors with STK11 mutations and a myxoid background. These data demonstrate that female adnexal tumors of probable Wolffian origin are morphologically and immunohistochemically diverse, but infrequently harbor pathogenic mutations. However, their lack of mutations in contrast to their mimickers may be a valuable tool in diagnostically difficult cases.
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http://dx.doi.org/10.1038/s41379-019-0375-9DOI Listing
April 2020

Loss of microfibril-associated protein 5 (MFAP5) expression in colon cancer stroma.

Virchows Arch 2020 Mar 18;476(3):383-390. Epub 2019 Aug 18.

Department of Pathology, University of Chicago Medical Center, Chicago, IL, USA.

MFAP5, a 25-kD microfibril-associated glycoprotein that is involved in elastic microfibril assembly, has been demonstrated to be significantly downregulated in tumor stroma by previous gene expression study. The aim of this study was to confirm the reduced expression of MFAP5 in colonic tumor stroma using immunohistochemistry and to explore the utility of MFAP5 as a marker to facilitate diagnosing an invasive component versus pseudoinvasion in colon polyps. In all 19 colon cancer resection cases evaluated, while there was intact MFAP5 immunoreactivity in the uninvolved normal connective tissue, there was marked reduction of MFAP5 immunoreactivity in the desmoplastic stroma surrounding the invasive component. The difference in MFAP5 expression levels was most pronounced within the tumor, while a more heterogeneous expression pattern was observed at the tumor invasive front. Reduction of MFAP5 staining was also observed in the stroma around mucin pools in 6 out of 9 sections from mucinous adenocarcinomas and in areas with high-grade dysplasia. For the polypectomy cases, intact expression of MFAP5 was seen in the stroma surrounding the displaced adenomatous glands in 9 out of 12 polyps with pseudoinvasion. Loss of expression of MFAP5 was observed in the stroma surrounding small foci of invasive adenocarcinoma in 8 of 10 malignant polyps. MFAP5 is a useful marker that may help distinguish normal connective tissue from stroma within invasive colonic adenocarcinoma. MFAP5 may facilitate the distinction between pseudoinvasion and true invasive cancer in colonic adenomatous polyps with a sensitivity of 80% (confidence interval 44-96%) and a specificity of 75% (confidence interval 43-93%) in this small cohort.
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http://dx.doi.org/10.1007/s00428-019-02649-yDOI Listing
March 2020

MTAP immunohistochemistry is an accurate and reproducible surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant pleural mesothelioma.

Mod Pathol 2020 02 23;33(2):245-254. Epub 2019 Jun 23.

Department of Pathology, University of Chicago, 5841 S. Maryland Ave, Chicago, IL, USA.

Ancillary studies facilitate accurate diagnosis of morphologically challenging mesothelial proliferations. The current diagnostic algorithm proceeds from BAP1 immunohistochemistry to CDKN2A fluorescence in situ hybridization. While MTAP immunohistochemistry has recently shown promise as a surrogate for CDKN2A fluorescence in situ hybridization, it has been examined in only a few single-institution studies. Furthermore, there are no published reports on interobserver agreement or interlaboratory reproducibility for MTAP immunohistochemistry. We performed MTAP immunohistochemistry on 20 benign mesothelial lesions and 99 malignant mesotheliomas from five mesothelioma centers in four countries, and each MTAP stain was independently interpreted by four pathologists. CDKN2A fluorescence in situ hybridization data were available for a subset of cases, and a subset of cases was subjected in MTAP immunohistochemistry in multiple laboratories to assess interlaboratory reproducibility. Interobserver agreement in MTAP immunostain interpretation was excellent for all mesothelial lesions (kappa: 0.85) and for malignant mesothelioma cases only (kappa: 0.82). Interlaboratory reproducibility was also excellent (kappa values for paired protocols: 0.77-0.89). MTAP loss by immunohistochemistry was 78% sensitive and 96% specific for CDKN2A homozygous deletion. MTAP immunohistochemistry is a reliable surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant mesothelioma. Interobserver agreement is excellent for interpretation of MTAP staining, and protocols performed in different laboratories yield concordant MTAP staining results. Rare cases with immunohistochemical MTAP loss may retain normal CDKN2A copy number, and the MTAP staining results should be correlated with clinicopathologic findings and other ancillary studies.
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http://dx.doi.org/10.1038/s41379-019-0310-0DOI Listing
February 2020

Fine-needle aspiration of dermatofibrosarcoma protuberans metastasizing to hemithorax with superior vena cava compression: Case report and literature review.

Diagn Cytopathol 2019 Aug 27;47(8):797-802. Epub 2019 Mar 27.

Department of Pathology, The University of Chicago, Chicago, Illinois.

Dermatofibrosarcoma protuberans (DFSP) is a low-grade spindle cell tumor of the skin commonly arising on the trunk and extremities which tends to be slow growing yet locally aggressive. DFSPs are associated with a good prognosis when surgical excision with negative margins is achieved. Although local recurrences occur up to 50% of incompletely resected cases, distant metastases are very rare. Here, we report a case of DFSP metastasizing to the right hemithorax diagnosed by an endobronchial ultrasound-guided fine-needle aspiration (FNA) 9 years after initial presentation. The aspirate showed a bland spindle cell proliferation that was morphologically similar to the original skin excision; the storiform pattern was particularly prominent in tumor-tissue fragments in the cellblock. Immunostaining showed strong, diffuse positivity for CD34. Molecular studies demonstrated a characteristic COL1A1/PDGFB fusion in both original and metastatic specimens. A review of the literature revealed that metastatic DFSP most often involves the lungs, occurs usually in cases with fibrosarcomatous transformation and after a local recurrence, and presents on average 4.5 years after the original diagnosis. This case did not show fibrosarcomatous transformation or local recurrence prior to metastasis 9 years later. In summary, it is important to consider the potential for metastases years after a nonrecurring primary DFSP, despite its rarity. Cytologic features when complemented by ancillary studies and awareness of the patient's prior clinical history permit a confident diagnosis of metastatic DFSP by FNA. In addition, by confirming the characteristic translocation, tyrosine-kinase inhibitor imatinib can provide additional treatment options for unresectable metastatic DFSP.
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http://dx.doi.org/10.1002/dc.24179DOI Listing
August 2019

Tumor PD-L1 expression in malignant pleural and peritoneal mesothelioma by Dako PD-L1 22C3 pharmDx and Dako PD-L1 28-8 pharmDx assays.

Hum Pathol 2019 05 20;87:11-17. Epub 2019 Feb 20.

Department of Pathology, University of Utah, Salt Lake City, UT 84112; ARUP Laboratories, Salt Lake City, UT, 84108.

Malignant mesothelioma (MM) is an aggressive neoplasm with poor prognosis. The Dako PD-L1 22C3 and 28-8 pharmDx assays are approved by the US Food and Drug Administration (FDA) as companion and complementary diagnostics for the anti-PD-1 drugs pembrolizumab and nivolumab, respectively. Data from multiple clinical trials indicate that immunotherapy has antitumor activity in advanced malignant pleural (MPM) and peritoneal mesothelioma (MPeM). However, large studies of PD-L1 expression in MM using the FDA-approved anti-PD-L1 assays are lacking. We stained tissue microarray sections (N = 125; 112 MPM and 13 MPeM) using 2 FDA-approved clinical immunohistochemical makers for PD-L1 expression: Dako PD-L1 22C3 pharmDx and Dako PD-L1 28-8 pharmDx. Overall, 22% (27/125) of MMs were positive using the 22C3 assay, whereas 27% (32/117) were positive using the 28-8 assay, using a tumor proportion score cutoff of 1%. Tumor cell PD-L1 expression was strongly correlated with PD-L1 expression on tumor-associated immune cells. No significant difference in PD-L1 expression was observed by patient sex, age, treatment history, pathologic stage, or histologic subtype. However, the proportion of cases positive for PD-L1 expression was higher among MPeM compared to MPM (P = .007 for 22C3 assay; P = .04 for 28-8 assay). PD-L1 is expressed in a substantial proportion of MM cases, as measured by FDA-approved companion assays for widely used immunotherapeutic drugs. PD-L1 expression is particularly prevalent in MPeM. These findings support large clinical studies to further examine PD-L1 as a biomarker for a subset of MM patients that may benefit from immunotherapy.
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http://dx.doi.org/10.1016/j.humpath.2019.02.001DOI Listing
May 2019

Immunohistochemical evaluation of nuclear 5-hydroxymethylcytosine (5-hmC) accurately distinguishes malignant pleural mesothelioma from benign mesothelial proliferations.

Mod Pathol 2019 03 12;32(3):376-386. Epub 2018 Oct 12.

Department of Pathology, University of Chicago, 5841 S. Maryland Ave, Chicago, Illinois, USA.

Accurate distinction of benign mesothelial proliferations from malignant mesothelioma remains a diagnostic challenge. Sequential use of BAP1 immunohistochemistry and CDKN2A fluorescence in situ hybridization is specific for diagnosis of mesothelioma, but fluorescence in situ hybridization is both costly and time-consuming. Early data indicate that mesothelioma shows extensive loss of nuclear 5-hydroxymethylcytosine (5-hmC). We studied 49 cases of mesothelioma (17 epithelioid mesothelioma, 22 biphasic mesothelioma, and 10 sarcomatoid mesothelioma) and 23 benign mesothelial proliferations using a 5-hmC single immunohistochemical stain, CAM5.2/5-hmC double immunohistochemical stain, and BAP1 immunohistochemistry. Estimations of extent of 5-hmC loss were made using the 5-hmC single stain and CAM5.2/5-hmC double stain, and extent of nuclear 5-hmC loss was definitively quantitated in at least 1000 cells per case. Mean nuclear 5-hmC loss in mesothelioma (84%) was significantly greater than in benign mesothelial proliferations (4%) (p < 0.0001). Using 5-hmC loss in > 50% of tumor nuclei to define the diagnosis of mesothelioma, 5-hmC immunohistochemistry showed sensitivity of 92% and specificity of 100%. An immunopanel including 5-hmC and BAP1 immunohistochemistry achieved sensitivity of 98% and specificity of 100%. Extensive nuclear 5-hmC loss is sensitive and specific for mesothelioma in the differential diagnosis with benign mesothelial proliferations. In challenging mesothelial lesions, immunohistochemical studies showing either extensive 5-hmC loss or BAP1 loss indicate a diagnosis of mesothelioma, precluding the need for CDKN2A fluorescence in situ hybridization in a considerable number of cases.
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http://dx.doi.org/10.1038/s41379-018-0159-7DOI Listing
March 2019

Ubiquitin Immunostaining in Thyroid Neoplasms Marks True Intranuclear Cytoplasmic Pseudoinclusions and May Help Differentiate Papillary Carcinoma from NIFTP.

Head Neck Pathol 2018 Dec 6;12(4):522-528. Epub 2018 Mar 6.

Department of Pathology, The University of Chicago Medical Center, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA.

Papillary thyroid carcinoma (PTC) is defined by an invasive growth pattern and classic nuclear features: enlarged, grooved, overlapping nuclei with chromatin clearing and intranuclear cytoplasmic pseudoinclusions (INCP). True INCPs are characteristic of PTC, but may infrequently be seen in noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP). Nuclear abnormalities that mimic INCP ("pseudo-pseudoinclusions") are common in a variety of thyroid lesions. H&E and ubiquitin-stained whole tissue sections of classic PTC (n = 25) and NIFTP (n = 35) were evaluated. On H&E, true INCPs were present in all (100%) PTCs and absent in all NIFTPs (0%). Pseudo-pseudoinclusions were present in 13 (37%) NIFTPs. In 24 (96%) PTCs, ubiquitin was strongly expressed within INCPs. In NIFTPs, optically clear nuclei or pseudo-pseudoinclusions did not express ubiquitin (0/35). Occasionally, nuclear vacuoles in NIFTP demonstrated a marginated staining pattern, in which strong ubiquitin expression was seen at the periphery of the nucleus, but the central pale area was negative. In addition, 2 NIFTPs demonstrated intrafollicular psammomatoid calcifications which were strongly ubiquitin-positive. Psammoma bodies in PTC were ubiquitin-negative in the majority of cases. We report a previously undescribed finding: strong ubiquitin expression in true INCPs in PTC, absence of true INCPs in NIFTP, and absence of ubiquitin expression in pseudo-pseudoinclusions in NIFTP. This finding supports the difference between true INCPs (found only in PTC) and pseudo-pseudoinclusions (found in NIFTP). Using strict histologic criteria and ubiquitin immunostaining, the presence of true pseudoinclusions may exclude a diagnosis of NIFTP. Caution should be exercised when interpreting nuclear vacuoles or pseudo-pseudoinclusions.
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http://dx.doi.org/10.1007/s12105-018-0905-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232225PMC
December 2018

Nuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: a multi-institutional study.

Mod Pathol 2018 04 12;31(4):598-606. Epub 2018 Jan 12.

Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

A recently described nuclear grading system predicted survival in patients with epithelioid malignant pleural mesothelioma. The current study was undertaken to validate the grading system and to identify additional prognostic factors. We analyzed cases of epithelioid malignant pleural mesothelioma from 17 institutions across the globe from 1998 to 2014. Nuclear grade was computed combining nuclear atypia and mitotic count into a grade of I-III using the published system. Nuclear grade was assessed by one pathologist for three institutions, the remaining were scored independently. The presence or absence of necrosis and predominant growth pattern were also evaluated. Two additional scoring systems were evaluated, one combining nuclear grade and necrosis and the other mitotic count and necrosis. Median overall survival was the primary endpoint. A total of 776 cases were identified including 301 (39%) nuclear grade I tumors, 354 (45%) grade II tumors and 121 (16%) grade III tumors. The overall survival was 16 months, and correlated independently with age (P=0.006), sex (0.015), necrosis (0.030), mitotic count (0.001), nuclear atypia (0.009), nuclear grade (<0.0001), and mitosis and necrosis score (<0.0001). The addition of necrosis to nuclear grade further stratified overall survival, allowing classification of epithelioid malignant pleural mesothelioma into four distinct prognostic groups: nuclear grade I tumors without necrosis (29 months), nuclear grade I tumors with necrosis and grade II tumors without necrosis (16 months), nuclear grade II tumors with necrosis (10 months) and nuclear grade III tumors (8 months). The mitosis-necrosis score stratified patients by survival, but not as well as the combination of necrosis and nuclear grade. This study confirms that nuclear grade predicts survival in epithelioid malignant pleural mesothelioma, identifies necrosis as factor that further stratifies overall survival, and validates the grading system across multiple institutions and among both biopsy and resection specimens. An alternative scoring system, the mitosis-necrosis score is also proposed.
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http://dx.doi.org/10.1038/modpathol.2017.170DOI Listing
April 2018

PAX8 Expression in a Subset of Malignant Peritoneal Mesotheliomas and Benign Mesothelium has Diagnostic Implications in the Differential Diagnosis of Ovarian Serous Carcinoma.

Am J Surg Pathol 2017 Dec;41(12):1675-1682

*Department of Pathology, The University of Chicago, Chicago, IL †Department of Pathology and Laboratory Medicine, Wisconsin Institute for Medical Research, The University of Wisconsin-Madison, Madison, WI.

Distinguishing malignant peritoneal mesothelioma (MPM) from serous carcinoma involving the peritoneum remains a diagnostic challenge, particularly in small biopsy and cytology specimens. In this distinction, PAX8 expression has been regarded as a specific marker of serous carcinoma. In addition, BAP1 loss is reportedly specific to MPM, in the distinction from both benign mesothelial lesions and ovarian serous tumors (OSTs). Using immunohistochemistry, we examined PAX8 and BAP1 expression in 27 MPMs, 25 cases of benign mesothelium, and 45 OSTs. Five MPMs were PAX8 (5/27, 18%), while 8 cases of benign mesothelium expressed PAX8 (8/25, 32%). PAX8 expression in mesothelium was significantly more common in women than in men (P=0.01). Sixteen MPMs exhibited BAP1 loss (16/25, 64%), while BAP1 was retained in all benign mesothelium and all OSTs. All cases of PAX8 mesothelium were negative for expression of estrogen receptor. These data show that PAX8 is expressed in both benign and malignant mesothelium, and that BAP1 loss is highly specific for MPM, in the differential with both benign mesothelial proliferations and OTSs. These results also have implications for primary diagnosis and for pathologic staging of OST. Caution should be applied when PAX8 expression is used to distinguish mesothelial and serous proliferations, and BAP1 loss may be confirmatory in cases where mesothelioma is favored.
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http://dx.doi.org/10.1097/PAS.0000000000000935DOI Listing
December 2017

An Ovarian Adenocarcinoma With Combined Low-grade Serous and Mesonephric Morphologies Suggests a Müllerian Origin for Some Mesonephric Carcinomas.

Int J Gynecol Pathol 2018 Sep;37(5):448-459

Department of Pathology, The University of Chicago, Chicago, Illinois (D.B.C, T.K., R.R.L.) Department of Pathology, University of California-San Francisco, San Francisco, California (N.M.J.).

Mesonephric carcinomas are rare adenocarcinomas of the female genital tract that occur most commonly in the uterine cervix. They are classically thought to arise from benign mesonephric remnants, and are rarely reported at other sites in the gynecologic tract. Here we present an interesting biphenotypic ovarian adenocarcinoma with intimately associated but distinct components of both low-grade serous carcinoma and mesonephric-like carcinoma. A serous borderline tumor was present adjacent to the invasive carcinoma, and no benign mesonephric precursors were identified. Numerous invasive peritoneal metastases were present, including multiple metastases with both low-grade serous and mesonephric-like elements. Consistent with recent reports, foci of mesonephric-like carcinoma were morphologically and immunohistochemically identical to classic mesonephric carcinoma of the cervix. On molecular analysis, the serous borderline tumor, primary and metastatic low-grade serous carcinoma, and primary and metastatic mesonephric-like carcinoma each harbored a shared NRAS p.Q61R hotspot mutation, shared gains in chromosome 1q and 18p, and shared losses in chromosomes 1p, 18q, and 22. These shared molecular features indicate a clonal relationship between all morphologic elements of this ovarian adenocarcinoma, suggesting that at least some mesonephric carcinomas may arise from Müllerian precursors.
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http://dx.doi.org/10.1097/PGP.0000000000000444DOI Listing
September 2018

Guidelines for Pathologic Diagnosis of Malignant Mesothelioma 2017 Update of the Consensus Statement From the International Mesothelioma Interest Group.

Arch Pathol Lab Med 2018 Jan 7;142(1):89-108. Epub 2017 Jul 7.

From the Department of Pathology, University of Chicago Medical Center, Chicago, Illinois (Drs Husain and Krausz); the Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona (Dr Colby, emeritus); the Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston (Dr Ordóñez); the Department of Pathology, University of Texas Medical Branch, Galveston (Dr Allen); the Department of Cellular Pathology, University Hospital of Wales and Cardiff University, Cardiff, South Glamorgan, Wales (Dr Attanoos); the Department of Pathology, Mount Sinai Medical Center, New York, New York (Dr Beasley); the Department of Pathology, University of Vermont College of Medicine, Burlington (Dr Butnor); the Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (Dr Chirieac); the Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada (Dr Churg); the Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (Dr Dacic); Centre National Référent MESOPATH Departement de Biopathologie, Lyon Cedex, France (Dr Galateau-Sallé); the Department of Pathology, University Hospital of Wales, Penarth, South Glamorgan, Wales (Dr Gibbs); the Department of Pathology, PhenoPath Laboratories, Seattle, Washington (Dr Gown); the Department of Pathology & Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, (Dr Litzky); the Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California (Drs Marchevsky and Walts); the Department of Histopathology, Royal Brompton & Harefield National Health Service Foundation Trust and the National Heart and Lung Institute, Imperial College, Chelsea, London, England (Dr Nicholson); the Department of Pathology, Duke University Medical Center, Durham, North Carolina (Dr Roggli); the Department of Pathology, University of Pittsburgh, and the VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania (Dr Sharma); the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Travis); and the Department of Pathology, University of Virginia Medical Center, Charlottesville (Dr Wick).

Context: - Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose.

Objective: - To provide updated, practical guidelines for the pathologic diagnosis of MM.

Data Sources: - Pathologists involved in the International Mesothelioma Interest Group and others with an interest and expertise in the field contributed to this update. Reference material included up-to-date, peer-reviewed publications and textbooks.

Conclusions: - There was discussion and consensus opinion regarding guidelines for (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) recognition of the key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid MM, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels employed is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Depending on the morphology, immunohistochemical panels should contain both positive and negative markers for mesothelial differentiation and for lesions considered in the differential diagnosis. Immunohistochemical markers should have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic and membranous markers). Selected molecular markers are now being used to distinguish benign from malignant mesothelial proliferations. These guidelines are meant to be a practical diagnostic reference for the pathologist; however, some new pathologic predictors of prognosis and response to therapy are also included.
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http://dx.doi.org/10.5858/arpa.2017-0124-RADOI Listing
January 2018

Melanotic PEComa of the Sinonasal Mucosa With NONO-TFE3 Fusion: An Elusive Mimic of Sinonasal Melanoma.

Am J Surg Pathol 2017 May;41(5):717-722

*Department of Pathology, University of Chicago Medicine §Chicago Otolaryngology Associates, Chicago ‡Dermatopathology, Midwest Diagnostic Pathology, Park Ridge, IL †Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI ∥Department of Pathology/Microbiology, Pediatrics, and Orthopaedic Surgery, 983135 Nebraska Medical Center, University of Nebraska, Omaha, NE.

Perivascular epithelioid cell neoplasms (PEComas) are a family of mesenchymal tumors with features of both smooth muscle and melanocytic differentiation, with or without true melanin pigment. The highly variable morphology of PEComas results in a broad differential diagnosis that is also dependent on anatomic site. A subset demonstrates rearrangements involving the TFE3 (Xp11) locus, which can be used in diagnostically difficult cases. Here we describe a case of a melanotic PEComa with NONO-TFE3 fusion occurring in the sinonasal mucosa, as demonstrated by both next-generation sequencing and molecular cytogenetic studies. This case is the first of its kind in the literature and only the second documented PEComa harboring a NONO-TFE3 rearrangement. In light of unequivocal molecular ancillary studies, this case illustrates that PEComa must enter the differential for pigmented lesions of the sinonasal mucosa, where malignant melanoma would be much more likely to occur.
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http://dx.doi.org/10.1097/PAS.0000000000000778DOI Listing
May 2017

BAP1 immunohistochemistry has limited prognostic utility as a complement of CDKN2A (p16) fluorescence in situ hybridization in malignant pleural mesothelioma.

Hum Pathol 2017 02 19;60:86-94. Epub 2016 Oct 19.

Department of Pathology, University of Chicago Medicine, Chicago, IL 60637. Electronic address:

BRCA-associated protein 1 (BAP1) immunohistochemistry (IHC) and CDKN2A (p16) fluorescence in situ hybridization (FISH) have shown clinical utility in confirming the diagnosis of malignant pleural mesothelioma (MPM), but the role for using these 2 markers to guide clinical management is not yet clear. Although p16 loss is predictive of poor prognosis, there is controversy as to whether BAP1 loss is predictive of a more favorable prognosis; how these results interact with one another has not been explored. We performed CDKN2A FISH on a previously published tissue microarray on which we had performed BAP1 IHC, revealing combined BAP1/p16 status for 93 MPM cases. As expected, BAP1 IHC in combination with CDKN2A FISH resulted in high sensitivity (84%) and specificity (100%) for MPM, and p16 loss was an independent predictor of poor survival (hazard ratio, 2.2553; P = .0135). There was no association between BAP1 loss and p16 loss, as 26%, 28%, 30%, and 16% of overall cases demonstrated loss of BAP1 alone, loss of p16 alone, loss of both BAP1 and p16, or neither abnormality, respectively. Although multivariate analysis demonstrated that BAP1 IHC is not an independent predictor of prognosis, when viewed in combination with homozygous CDKN2A deletion, risk stratification was evident. More specifically, patients with CDKN2A disomy and loss of BAP1 expression had improved outcomes compared with those with CDKN2A disomy and retained BAP1 expression (hazard ratio, 0.2286; P = .0017), and this finding was notably evident among epithelioid cases. We conclude that BAP1 IHC provides prognostic information within the context of CDKN2A FISH that may have clinical utility beyond diagnosis.
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http://dx.doi.org/10.1016/j.humpath.2016.09.026DOI Listing
February 2017

Primary epithelioid sarcoma of the kidney and adrenal gland: report of 2 cases with immunohistochemical and molecular cytogenetic studies.

Hum Pathol 2017 03 18;61:158-163. Epub 2016 Oct 18.

Department of Pathology, University of Chicago Medicine, Chicago, IL, USA.

Epithelioid sarcoma (ES) is a malignant mesenchymal neoplasm with some morphologic or immunophenotypic evidence of epithelial differentiation. The "classic" subtype occurs in younger patients, often in distal extremities as compared with the "proximal" type. Tumors of the proximal type primarily arising in solid organs are rare with only few case reports in the literature. We report 2 cases of primary ES in the kidney of a 27-year-old woman and the adrenal gland of a 73-year-old man. Clinical examination and imaging, including computed tomography and positron-emission tomography, did not reveal tumor elsewhere in both cases. Histologic features were those of ES, proximal type with epithelioid/rhabdoid phenotype. Immunohistochemical study in both cases showed strong, diffuse expression of epithelial markers, CD34, and CD31. Nuclear expression of SMARCB1 protein was lost, but fluorescence in situ hybridization analysis was negative for SMARCB1 deletion. We believe that these are the first reports of primary kidney and adrenal gland ES.
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http://dx.doi.org/10.1016/j.humpath.2016.09.024DOI Listing
March 2017

Disseminated Malignant Rhabdoid Tumor of the Head and Neck.

Head Neck Pathol 2017 Jun 8;11(2):224-227. Epub 2016 Sep 8.

Department of Pathology, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA.

Disseminated extrarenal malignant rhabdoid tumors of the head and neck are very rare, but aggressive tumors. Although the features on radiological imaging may be nonspecific, the imaging is useful for assessing the extent of tumor involvement. Key pathologic features are those of a cellular "blue cell tumor" with variable rhabdoid appearance. These cells express a combination of markers usually viewed as characteristic of diverse lines of differentiation, including EMA, cytokeratins, smooth muscle markers, and GFAP, and occasionally synaptophysin. At a molecular level, the entity is defined by mutations or alterations in the SMARB1/INI1 gene resulting in loss of INI1 expression. Diagnostic features include rhabdoid cells, expression of keratin with absence of desmin, S100 protein and CD34, and loss of INI1 expression. These features are exemplified in this sine qua non radiology-pathology correlation article.
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http://dx.doi.org/10.1007/s12105-016-0754-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429277PMC
June 2017

A randomized phase I trial of nanoparticle albumin-bound paclitaxel with or without mifepristone for advanced breast cancer.

Springerplus 2016 30;5(1):947. Epub 2016 Jun 30.

Section of Hematology/Oncology, Department of Medicine, The University of Chicago, 5841 S. Maryland Ave., MC 2115, Chicago, IL 60637 USA.

Purpose: Glucocorticoid receptor (GR) overexpression is associated with poor prognosis ER-negative breast cancer. GR antagonism with mifepristone increases chemotherapy-induced breast cancer cell death, therefore we conducted a phase I clinical trial of mifepristone and nab-paclitaxel in advanced breast cancer.

Methods: A novel randomized phase I design was used to assess the effect of mifepristone on nab-paclitaxel pharmacokinetics and toxicity. Patients were randomized to placebo or mifepristone for the first cycle; mifepristone was given to all for subsequent cycles.

Results: Nine patients were enrolled. All were found to have a twofold or greater increase in serum cortisol after mifepristone administration, reflecting effective GR inhibition. Neutropenia occurred at both nab-paclitaxel dose levels studied (100 and 80 mg/m(2)), and was easily managed with dose reduction and/or growth factor administration. Pharmacokinetic data suggest an interaction between nab-paclitaxel and mifepristone in some patients. Two patients had complete responses (CR), three partial responses (PR), one stable disease (SD), and three progressive disease (PD). Immunohistochemical staining for GR found six of nine tumors were GR-positive. All six GR-positive tumors were triple-negative at the time of recurrence. Of these six patients, two had CRs, two PRs, one SD, and one PD.

Conclusions: GR appears to be a promising target in TNBC, and GR inhibition plus chemotherapy produces manageable toxicity. While neutropenia was observed in some, a nab-paclitaxel dose of 100 mg/m(2) plus mifepristone 300 mg was found to be tolerable, and a randomized phase II trial of nab-paclitaxel with/without mifepristone is planned in GR-positive advanced TNBC.
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http://dx.doi.org/10.1186/s40064-016-2457-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929099PMC
July 2016

Epigenetic regulation of SMARCB1 By miR-206, -381 and -671-5p is evident in a variety of SMARCB1 immunonegative soft tissue sarcomas, while miR-765 appears specific for epithelioid sarcoma. A miRNA study of 223 soft tissue sarcomas.

Genes Chromosomes Cancer 2016 10 24;55(10):786-802. Epub 2016 Jun 24.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Complete/partial loss of SMARCB1 nuclear-immunopositivity is characteristic of a certain subset of soft tissue sarcomas (STSs). Our previous work showed that oncomiRs-206,-381, and 671-5p could silence the SMARCB1 mRNA and protein expression and that they display significant overexpression in epithelioid sarcomas (ESs). MiR-765 was overexpressed too, but functionally was inactive in the silencing. In the current work, using quantitative PCR, we conducted a miRNA study of 51 ESs, 20 rhabdoid tumors (RTs), 20 synovial sarcomas (SSs), 15 malignant peripheral nerve sheath tumors (MPNSTs), 11 myoepithelial carcinomas (MECs), and 10 extraskeletal myxoid chondrosarcomas (EMCSs) with complete/partial loss of SMARCB1 nuclear immunostain, in contrast to controls (SMARCB1-immunopositive) of 96 STSs, 13 melanomas and 10 sarcomatoid carcinomas. The SMARCB1 genetic status of ESs was determined by MLPA and FISH. A subset of ESs (5/51) showed biallelic deletion of SMARCB1 with no overexpression of any miRNA, suggesting these tumors could be the counterpart of pediatric RT, at least genetically. Another subset (5/51) was genetically either intact or monoallelic deleted with at least threefold overexpression of one of miR-206,-381,-671-5p, suggesting epigenetic regulation only. 39/51 ESs had a biallelic deletion (>20% by FISH and/or by MLPA) but with overexpressed miR-206,-381, and 671-5p, suggesting intratumoral heterogeneity, i.e., both genetic and epigenetic regulation. At least threefold overexpression of one of miR-206,-381, and 671-5p was detected in all MPNSTs, EMCSs, SSs and 7 MCs. Except for ESs, four SSs and one MPNST, there was no event above threefold overexpression of miR-765 among all 195 tested tumors. Our results suggest a general role of miR-206,-381, and 671-5p in SMARCB1 gene silencing of ES, MC, EMCS, MPNST and SS. In the future, miR-765 could possibly be a diagnostic tool for ES because of its 97% specificity and 80% sensitivity. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/gcc.22379DOI Listing
October 2016

MYC Amplification in Angiosarcoma Arising from an Arteriovenous Graft Site.

Case Rep Pathol 2015 24;2015:537297. Epub 2015 Nov 24.

Department of Pathology, University of Chicago, 5841 S Maryland Avenue, MC 6161, Chicago, IL 60637, USA.

Angiosarcoma arising in association with an arteriovenous graft (AVG) or fistula is a unique clinicopathologic scenario that appears to be gaining recognition in the literature. Among reported cases, none has described high-level MYC gene amplification, a genetic aberration that is increasingly unifying the various clinicopathologic subdivisions of angiosarcoma. We therefore report the MYC gene status in a case of angiosarcoma arising at an AVG site.
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http://dx.doi.org/10.1155/2015/537297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670641PMC
December 2015